The development and spread of drug resistance in malaria parasites has become a major obstacle in the treatment and control of the disease that causes approximately 300 million infections and up to 3 million deaths per-year. A better understanding of factors that influence the emergence and survival of drug resistant parasites will help develop intervention strategies that minimize the risk of drug resistance and prolong the effective life of anti-malarial drugs. The ability for P. falciparum parasites to vary the surface protein, PfEMP1, antigenically is important for immune evasion and pathogenesis. PfEMP1, which is encoded by the var genes, allows the parasitized cells to adhere to the linings of blood vessels thereby avoiding destruction by the spleen. PfEMP1 also stimulates a host specific antibody response that kills parasites expressing the protein, while parasites that have switched to express a different variant survive. We hypothesize that antigenic variation of PfEMP1 also plays an important role in the survival and spread of drug resistant malaria parasites. This proposal aims to investigate the process involved in PfEMP1 antigenic variation, the switch rates of these antigens, and the role that PfEMP1 switching and the corresponding host anti-PfEMP1 responses play in the emergence, evolution, maintenance and spread of drug resistance in Plasmodium falciparum. We will use experimental procedures and mathematical simulation models to investigate: 1) Investigate antigenic variation and its role in parasite survival by examining the var gene switching process and associated switch rates in P. falciparum parasites from ex vivo samples of defined strains and from various regions of the world. 2) Investigate the transcribed var genes in parasite populations of pre-treatment and post-treatment recrudescence's to provide experimental proof for the role of antigenic switching in the survival of drug resistant parasites causing treatment failures. 3) Investigate the role of PfEMP1 in determining the parasite population and spread of drug resistance by examining the linkage between PfEMP1 and drug resistance markers in field isolates. 4) Investigate the importance of factors such as antigenic variation, parasite diversity and treatment strategies for the establishment and spread of drug resistant parasite populations within communities, by modeling in-host dynamics and transmission. The outcome of this research will help to develop intervention strategies that minimize the risk of drug resistance and prolong the effective life of anti-malarial drugs. The project has the potential to benefit the health of a substantial proportion of the world's population.